The genetics of sensitization of mice to stimulation by cocaine and by amphetamine will be analyzed with respect to both the metabolism of these agents and changes in the turnover of brain catecholamines. In vitro and in vivo studies of metabolism will be carried out with the aid of thin layer and gas-liquid chromatography. The effects of sensitization on the activity of striatal tyrosine hydroxylase and on the conversion of labeled tyrosine to catecholamines will be determined. Genetic differences in cocaine-induced liver damage will be examined. In order to establish the mechanism of liver damage and its relationship to the metabolism of cocaine, we will test metabolites of cocaine, such as nor-cocaine and benzoyl ecgonine. Inducers such as phenobarbital and benzypyrene will be administrated in order to increase the rate of cocaine metabolism. Work on the genetics of acute and chronic responses to morphine will be continued. Attempts will be made to obtain defined congenic lines that permit identification of the genetic determinants of these responses in mice. BIBLIOGRAPHIC REFERENCES: Polsky, R. and Shuster, L. Preparation and characterization of two isozymes of choline acetyltransferase from squid head ganglia. I. Purification and properties. Biochim. Biophys. Acta 445, 25-42 (1976). Polsky, R. and Shuster, L. Preparation and characterization of two isozymes of choline acetyltransferase from squid head ganglia. II. Self-association, molecular weight determinations, and studies with inactivating antisera. Biochim. Biophys. Acta 445, 43-66 (1976).